腹水治疗指南

SPECIAL ARTICLE The Management of Ascites in Cirrhosis: Report on the Consensus Conference of the International Ascites Club Kevin P. Moore,1 Florence Wong,2 Pere Gines,3 Mauro Bernardi,4 Andreas Ochs,5 Francesco Salerno,6 Paolo Angeli,7 Michael Porayko,8 Richard Moreau,9 Guadelupe Garcia-Tsao,10 Wladimiro Jimenez,11 Ramon Planas,12 and Vicente Arroyo3 Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tubercu- losis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restrictionanddiuretic therapywithspironolactoneoranequivalent inthefirst instance.Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepaticportosystemicstentshunt(TIPS).SuccessfulplacementofTIPSresults in improvedrenal function,sodiumexcretion,andgeneralwell-beingof thepatientbutwithoutprovensurvivalbenefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis. (HEPATOLOGY 2003;38:258-266.) Ascites occurs in more than 50% of patients within10 years of the diagnosis of cirrhosis. Cirrhoticascites accounts for over 75% of patients who present with ascites, with the remaining 25% being due to malignancy (10%), cardiac failure (3%), pancreatitis (1%), tuberculosis (2%), or other rarer causes.1 There have been several changes in the clinical management of ascites over recent years. The recommendations put for- ward in this document were agreed on by an International Ascites Club Consensus Meeting on the management of ascites. This meeting was supported by an unconditional educational grant from Searle, Spain. These recommen- dations have been updated in line with subsequent recent publications of controlled clinical studies. Diagnosis and Investigation of Ascites All patients need investigation of the causes of ascites, even when cirrhosis is suspected. Ascitic fluid should be sent for the determination of albumin or protein concen- tration. To diagnose spontaneous bacterial peritonitis (SBP), ascitic fluid should be examined by microscopy and inoculated directly into blood culture bottles. An as- citic fluid neutrophil count of�250 polymorphonuclear cells/mm3 is diagnostic of SBP, but a Gram stain of the ascitic fluid is usually uninformative.2 Ascitic fluid from patients with suspected malignant or pancreatic ascites should be sent for cytology or measurement of amylase. Abbreviations: SBP, spontaneous bacterial peritonitis; HRS, hepatorenal syn- drome; PPH, postparacentesis effective hypovolemia; TIPS, transjugular intrahe- patic portosystemic shunt. From the 1Centre for Hepatology, Royal Free and University College Medical School, UCL, London, United Kingdom; 2Division of Gastroenterology, Toronto General Hos- pital, University of Toronto, Toronto, Canada; 3Liver Unit, Hospital Clinic, Barcelona and the University of Barcelona School of Medicine, Barcelona, Spain; 4Department Medicina Interna, Cardioangiologia, Epatologia, Alma Mater Studiorum–Universita` di Bologna, Italy; 5Department of Internal Medicine, University of Freiburg, Freiberg, Germany; 6Department of Internal Medicine, IRCCS Policlinico, University of Milan, Milan, Italy; 7Department of Clinical and Experimental Medicine, University of Padua, Padova, Italy; 8Department of Liver Transplantation, Thomas Jefferson Uni- versity, Philadelphia, PA; 9INSERM U-481 et Service d’Hepatologie, Hopital Beaujon, Clichy, France; 10Digestive Diseases Section, Yale University School of Medicine, New Haven, CT; 11Hormal Laboratory, Hospital Clinic, Barcelona and the University of Barcelona School of Medicine, Barcelona, Spain; and 12Department of Gastroenterol- ogy, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Received October 31, 2002; accepted May 7, 2003. Address reprint requests to: Kevin Moore, M.D., Centre for Hepatology, Royal Free and University College Medical School, UCL, Rowland Hill St., London NW3 2PF, England. E-mail: kmoore@rfc.ucl.ac.uk; fax: (44) 207-433-2877. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3801-0034$30.00/0 doi:10.1053/jhep.2003.50315 258 The use of ascitic fluid protein in the differential diag- nosis of the causes of ascites is overrated and misinter- preted. Conventionally, the type of ascites is divided into exudates and transudates in which the ascitic fluid protein concentration is �25 g/L or �25 g/L, respectively, to help in the differential diagnosis of the causes of ascites. However, many physicians assume that cardiac ascites will have a low ascitic protein, but this is rarely the case.3 Moreover, �15% of cases of cirrhotic ascites have an ascitic protein�25 g/L, and 20% of patients with malig- nancy have a low ascitic protein.4 The serum-ascites albu- min gradient (i.e., serum albumin� ascitic fluid albumin concentration) is more specific and sensitive at distin- guishing ascites due to portal (sinusoidal) hypertension (gradient �11 g/L) from that occurring as a result of different pathogenetic mechanisms, such as inflammation or peritoneal malignancy (gradient �11 g/L).5,6 Thus, ascitic fluid protein classified the causes of ascites correctly in 55% of cases, whereas serum-ascitic albumin gradient assigns the causes correctly 97% of the time.5 Definitions Uncomplicated Ascites. Uncomplicated ascites is as- cites that is not infected and that is not associated with the development of the hepatorenal syndrome (HRS). Grade 1 ascites is mild ascites only detectable by ultrasound ex- amination. Grade 2 ascites or moderate ascites is manifest by moderate symmetrical distension of abdomen. Grade 3 ascites is large or gross ascites with marked abdominal distension. Refractory Ascites. In 1996 the International Ascites Club defined “refractory ascites” as ascites that cannot be mobilized or the early recurrence of which cannot be sat- isfactorily prevented by medical therapy.7 It occurs in ap- proximately 5% to 10% of all cases of ascites.8 Two subgroups were identified as diuretic-resistant ascites and diuretic-intractable ascites.7 Additional findings fre- quently include type II HRS, dilutional hyponatremia, and wasting. The diagnostic criteria for refractory ascites have been slightly revised and are shown in Table 1. Prognosis of Cirrhosis With Ascites The development of ascites in patients with cirrhosis indicates a poor prognosis. The probability of death in cirrhotic patients hospitalized with ascites is �40% at 2 years.8 The prognosis is worse for those with refractory ascites and those who develop SBP.2 Treatment of Ascites: An Evidenced Based Approach The aim of treatment is to improve sodium balance or circulatory function until liver transplantation or until the disease runs its natural course. Patients with alcohol- induced cirrhosis who stop drinking may have a consid- erable improvement of liver function with resolution of ascites. Bed Rest In patients with cirrhosis and ascites, upright posture activates sodium-retaining systems and impairs renal per- fusion and sodium excretion. In one study, bed rest im- proved the response to diuretics.9 However, no clinical trials have shown that bed rest actually improves the effi- cacy of medical treatment. Sodium and Water Restriction A negative sodium balance can be achieved by dietary salt restriction or by increasing renal sodium excretion. With dietary salt restriction, loss of ascites occurs in 10% to 15% of patients.1 The use of low salt diets is almost universally recommended. However, this approach is not backed by the results of controlled clinical trials. Trials on Sodium Restriction. Severe sodium re- stricted diets are unpalatable, leading to poor patient compliance and poor nutrition. Five studies have com- pared the efficacy of different dietary regimes.10-14 Some societies readily adapt to a lower salt intake, whereas oth- ers are less compliant because of cultural differences. When severe dietary salt restriction (22 mmol/d) was compared with a less restricted diet, dietary salt restriction was associated with a shorter time for resolution of ascites but was associated with a higher incidence of diuretic- induced renal impairment and hyponatremia.10-13 In one controlled study, a slightly reduced salt diet (120 mmoles/d) was equally effective in patients with ascites when compared with a low-salt diet (50 mmol/d).14 There are no significant differences in survival between patients receiving salt-restricted or -unrestricted diets, al- Table 1. Revised Diagnostic Criteria of Refractory Ascites 1. Treatment duration: Patients must be on intensive diuretic therapy (spironolactone 400 mg/d and furosemide 160 mg/d) for at least 1 week and on a salt-restricted diet of less than 90 mmoles or 5.2 g of salt/d. 2. Lack of response: Mean weight loss of �0.8 kg over 4 days and urinary sodium output less than the sodium intake. 3. Early ascites recurrence: Reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization. 4. Diuretic-induced complications: Diuretic-induced hepatic encephalopathy is the development of encephalopathy in the absence of any other precipitating factor. Diuretic-induced renal impairment is an increase of serum creatinine by �100% to a value �2 mg/dL in patients with ascites responding to treatment. Diuretic-induced hyponatremia is defined as a decrease of serum sodium by �10 mmol/L to a serum sodium of �125 mmol/L. Diuretic induced hypo- or hyperkalemia is defined as a change in serum potassium to �3 mmol/L or �6 mmol/L despite appropriate measures. HEPATOLOGY, Vol. 38, No. 1, 2003 MOORE ET AL. 259 though the survival of patients with previous gastrointes- tinal bleeding was better in the low-salt group.13 A limitation of all such studies is patient compliance and being able to verify compliance. Water Restriction. Dilutional hyponatremia occurs in patients with decreased free water clearance, which is driven by nonosmotic baroceptor secretion of antidiuretic hormone secondary to effective central hypovolemia.15 Treatment of dilutional hyponatremia classically consists of water restriction. However, there have been no clinical trials to assess the effects of water restriction in patients with cirrhosis and dilutional hyponatremia, and indeed this treatment may exacerbate the central hypovolemia. Diuretics Anti-Mineralocorticoids. Secondary hyperaldoste- ronism is a major factor promoting renal sodium reten- tion16 in the distal tubules and collecting ducts of the nephron. Both controlled and uncontrolled clinical trials have shown that spironolactone is the drug of choice for the initial treatment.11-14,17,18 Spironolactone or canreno- ate (not available in North America) achieves a better natriuresis more often than “loop” diuretics such as furo- semide.18,19 The recommended initial dose of spironolac- tone is 100 to 200 mg once daily. When severe hyperaldosteronism (i.e., severe sodium retention) is present, the dosage may be increased to 400 mg/d.18,20,21 A therapeutic response is observed in �75% of patients. Gynecomastia is the main side effect of spironolactone, but metabolic acidosis with or without hyperkalemia may occur with renal impairment.22 Other Potassium-Sparing Diuretics. Amiloride and triamterene also act in the distal tubule. No controlled clinical trials on triamterene are available. Amiloride (20-60 mg/d) has been shown to be less effective than potassium canrenoate (150-500 mg/d).19 Loop Diuretics. Loop diuretics, such as furosemide, are frequently used as an adjunct to spironolactone ther- apy. The initial oral dose of furosemide is usually 20 to 40 mg/d, and is generally adjusted upward every few days up to a maximum of 160 mg/d. Furosemide may cause po- tassium depletion, metabolic hypochloremic alkalosis, and hyponatremia, as well as hypovolemia, leading to re- nal dysfunction.23,24 Assessing the Response to Diuretics. The mobiliza- tion of ascites is best assessed by daily weighing of the patient using accurate standardized weighing protocols. The rate of weight loss should not exceed �0.5 kg/d in the absence of edema, or �1 kg/d when edema is present.24 Medical treatment based on sodium-restricted diets, anti-mineralocorticoids, and loop diuretics achieves a response rate in up to 90% of patients without renal failure in controlled clinical trials.14,18,20 Paracentesis Paracentesis is used to treat ascites that has not re- sponded to medical therapy, to resolve large-volume as- cites rapidly, to enable easier ultrasound examination in patients with massive ascites, and to periodically treat re- fractory ascites. Trials of Paracentesis Versus Diuretics. There have been 5 randomized controlled trials comparing therapeu- tic paracentesis with diuretics in cirrhotic patients with ascites.25-29 These studies compared repeated large vol- ume paracentesis (5 L/d) with albumin infusion (6-8 g/L of ascites removed), and showed that paracentesis was more effective than diuretics in eliminating ascites and shortened the duration of hospitalization. Moreover, there were significantly fewer complications in the para- centesis-treated group compared with those treated with diuretics alone. These data have been confirmed by other studies.30 The issue of whether paracentesis should be repeated daily with 5-liter paracentesis or a single total paracentesis has been resolved.31,32 Tito` et al.31 showed that total paracentesis was as effective and as safe as re- peated partial paracentesis. Paracentesis causes an acute increase of cardiac output and a lowering of systemic vas- cular resistance, leading to a modest reduction of blood pressure.32 Pulmonary capillary wedge pressure decreases at �6 hours postparacentesis, whereas the right atrial pressure falls acutely following the onset of paracentesis, secondary to a reduction of intrathoracic pressure.32 Since postparacentesis effective hypovolemia (PPH) can occur hours or days after the procedure (see below), volume expansion should commence once the paracentesis has been completed. Total paracentesis shortens the period of hospitalization and can be done as an outpatient proce- dure. However, paracentesis does not obviate the need for diuretics. In one study, ascites recurred within 4 weeks postparacentesis in 18% of patients receiving diuretics immediately postparacentesis, compared with 93% in pa- tients receiving a placebo.33 Controversy of Volume Expansion. There is only one controlled trial comparing therapeutic paracentesis with and without volume expansion with follow-up over a few weeks. In this study, Gines et al. randomized pa- tients to receive repeated paracentesis (�5 L/d) plus albu- min or to repeated paracentesis alone.30 Side effects occurred in 30% of patients treated with paracentesis without albumin compared with 16% in those treated with albumin. Complications included a high incidence of renal impairment and hyponatremia and a marked el- evation of plasma renin and aldosterone concentrations. 260 MOORE ET AL. HEPATOLOGY, July 2003 If volume expansion is not given following paracentesis, patients may develop postparacentesis hypovolemia, lead- ing to hyponatremia and renal impairment. Postparacen- tesis volume expansion is recommended in patients with cirrhosis and ascites. The choice of fluid is, however, con- troversial. Human albumin solution is expensive and car- ries the risk of infection with noneradicated viruses or prion-related diseases. The use of albumin has been con- tested by the Practice Guidelines Committee of the Amer- ican Association for the Study of Liver Diseases.34 There have been 5 randomized controlled trials comparing vol- ume expansion with albumin with other forms of plasma expanders, including dextrans, collagen-based colloids, and hydroxyethyl starch.35-39 All studies have shown that synthetic plasma expanders are as effective as albumin at preventing the clinical complications of paracentesis, namely hyponatremia or renal impairment. However, Gines et al. showed that PPH, as defined by an increase in plasma renin activity or aldosterone concentrations, was prevented more effectively by albumin than synthetic plasma expanders.35 Contraindications and Complications of Paracen- tesis. Depite the fact that all published studies on para- centesis have excluded patients with SBP, renal failure, severe hepatic encephalopathy, thrombocytopenia, low blood pressure, or severe jaundice, there is no evidence that these complications should be considered as contra- indications for paracentesis in clinical practice. Thus, some physicians carry out a total paracentesis in patients with SBP to remove the infected fluid. However, there are no data to support this approach, and controlled studies are needed. There are no data to support the correction of mild coagulopathy with blood products prior to thera- peutic paracentesis,40 but caution is needed when severe thrombocytopenia is present. Acute complications fol- lowing paracentesis are sporadic. Bleeding occasionally occurs and may be fatal. Leakage of ascitic fluid should be managed by placing a purse-string suture around the opening and instructing the patient to lie with the punc- ture site uppermost. The most common complication is PPH and renal impairment. To date, there are no studies identifying factors that predict the development of post- paracentesis hypovolemia and renal impairment. Transjugular Intrahepatic Portosystemic Shunt (TIPS) Short-Term and Long-Term Effects of TIPS on Circulatory Function and Renal Function. TIPS, in which a self-expanding shunt is inserted to create a shunt between the hepatic vein (low pressure) and portal vein (high pressure), can lead to an improvement of renal func- tion and sodium excretion and the resolution of ascites.41 In the longer term it can also improve nitrogen balance and patient well being.42-44 It has largely replaced the use of surgically placed shunts. Insertion of a TIPS shunt leads to a marked increase of cardiac output, right atrial pressure, and pulmonary artery pressure,45 with a second- ary decrease of systemic vascular resistance and an increase in pulmonary vascular resistance and effective arterial blood volume. Sodium excretion and renal function im- prove over 4 weeks.46 Thus, serum creatinine decreased from 1.5 to 0.9 mg/dL in patients with refractory ascites post-TIPS.47 Complications. Immediate complications include capsule puncture and intra-abdominal bleeding. Late but common complications include shunt thrombosis and stenosis. The development of hepatic encephalopathy oc- curs in�30% of patients post-TIPS, but the incidence is higher in those patients with pre-TIPS encephalopathy and in those greater than 60 years old.48 TIPS increases the cardiac preload45 and may precipitate cardiac failure in pat